Antigenic shift is the process by which two different strains of influenza combine to form a new subtype having a mixture of the surface antigens of the two original strains. Because the human immune system has difficulty recognizing the new influenza strain, it may be highly dangerous.

Antigenic shift is contrasted with antigenic drift which is the natural mutation over time of known strains of influenza (or other things, in a more general sense) to evade the immune system.

Antigenic drift occurs in all types of influenza including influenza A, B and C. Antigenic shift, however, occurs only in influenza A because it infects more than just humans. Affected species include other mammals and birds, giving influenza A the opportunity for a major reorganization of surface antigens. Influenza B and C only infect humans, minimizing the chance to mutate drastically.

Flu strains are named after their types of hemagglutinin and neuraminidase surface proteins , so they will be called, for example, H3N2 for type-3 hemagglutinin and type-2 neuraminidase.

If two different strains of influenza infect the same cell simultaneously, their protein capsids and lipid envelopes are removed, exposing their RNA, which is then transcribed to DNA. The host cell then forms new viruses that combine antigens; for example, H3N2 and H5N1 can form H5N2 this way. Such combinations caused, for instance, the infamous Spanish Flu outbreak of 1918 which killed 40 million people worldwide. Influenza virus which have undergone antigenic shift have also gone on to cause the Asian Flu pandemic of 1957, the Hong Kong Flu pandemic of 1968, and the Swine Flu scare of 1976.

In 2004, scientists pointed out that the avian influenza virus might undergo an antigenic shift with the human flu virus and cause a global influenza pandemic like the one in 1918.

The term antigenic shift is specific to the influenza literature. In other viral systems, the same process is called reassortment or viral shift.